Pain is defined as an unpleasant sensory and emotional experience. However, pain can be informative and useful. For example, nociceptive pain is often indicative of injury (e.g., tissue damage) and such pain typically evokes escape or protective behaviors in animals or in a human in order to remove itself, or protect itself, from further exposure to the insult. However, inflammation, cellular and neuronal damage and other processes resulting from injury or disease can lead to states of chronic pathological pain and enhanced sensitivity called hyperalgesia, in which the perception of pain is exaggerated. In such cases, there is a need for new compounds, new methods and new inventions that treat pain and hyperalgesia.
In some cases, such as surgical procedures, the diminution or abolishment of nociceptive pain may be desired and the application of analgesia may be employed. A variety of compounds and medicines are known to be effective in alleviating nociceptive pain and some are analgesic such as opioids.
Post surgically, pain arising from the procedure, for example such as pain at or near the site of an incision, is common. In such cases, there is a desire to alleviate pain and thus there is a need for new compounds, new methods and new inventions that treat post-surgical and incisional pain.
The administration of opioids to treat pain is a well recognized and commonly employed therapy in medicine. Unfortunately, tolerance to opioids (tachyphylaxis) and opioid-induced hyperalgesia can often result during the course of therapy. In such patients, increasingly higher doses of opioids are needed to provide an acceptable level of pain relief. Administering these higher does, though, can cause adverse side effects implicating the safety concerns associated with opioids. Side effects associated with opioid administration may include respiratory depression, constipation, nausea, and vomiting. Safety concerns include the possibility of developing dependence, suffering withdrawal upon discontinuation of treatment, and the potential for abuse. Tachyphylaxis is a phenomenon in which the repeated administration of a drug, such as a narcotic analgesic, results in a rapidly appearing and marked decrease in the effectiveness of that drug. In opioid-induced hyperalgesia, prolonged administration of opioids also results in a paradoxical increase in pain, or a hypersensitivity to a stimulus that is thought to be unrelated to the original injury or insult. Opioid-induced tachyphylaxis and opioid-induced hyperalgesia have been well documented in animal models of nociception as well as in human clinical trials. These phenomena present significant clinical challenges for the treatment of pain and therefore new compounds, new methods and new inventions to treat pain and/or to alleviate hyperalgesia and tolerance are needed.
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are highly reactive small molecules that include, for example, oxygen ions and free radicals such as peroxide, hydroxyl radical and other species such as peroxynitrite (OONO−). Peroxynitrite is the product of the interaction between superoxide (O2−) and nitric oxide (NO). In cells, ROS and RNS form normally, as a by-product of normal metabolism, but they also play an important role in the pathogenesis of many disorders, including those affecting the lung, the central nervous system and skeletal muscle. In addition, during times of stress (such as, for example, hypoxia) ROS and/or RNS levels can increase significantly, which can lead to damage to cell components.
Peroxynitrite activity has been implicated in the development of opiate-induced antinociceptive (pain) tolerance (tachyphylaxis) (Muscoli et al., 2007, J Clin Invest 117:3530-3539). In 2007, Muscoli proposed that peroxynitrite formation is a key pathway in the development of narcotic analgesic tachyphylaxis. Previous attempts at reducing the damaging effects of peroxynitrite have been focused on flavonoids and simpler phenols, some of which have proven to be ineffective or toxic when administered to animals and man (Olmos et al., 2007, Med Res Rev 27:1-64; Choi et al., 2002, Phytother Res 16:232-235). Thus, collectively there exists a need for new compounds, new methods and new inventions that decrease the level or activity of reactive oxygen/nitrogen species, such as peroxynitrite.
Thus, there exists a need for compounds, compositions, and methods for preserving or extending opioid analgesia without opioid dose-escalation. Similarly, there exists a need for compounds, compositions, and methods that are dose-sparing with respect to opioid therapy. The current invention fulfills these needs.